A Strategy for Discovery of Endocrine Interactions with Application to Whole-Body Metabolism

Abstract

Inter-tissue communication via secreted proteins has been established as a vital mechanism for proper physiologic homeostasis. Here, we report a bioinformatics framework using a mouse reference population, the Hybrid Mouse Diversity Panel (HMDP), which integrates global multi-tissue expression data and publicly available resources to identify and functionally annotate novel circuits of tissue-tissue communication. We validate this method by showing that we can identify known as well as novel endocrine factors responsible for communication between tissues. We further show the utility of this approach by identification and mechanistic characterization of two new endocrine factors. Adipose-derived Lipocalin-5 is shown to enhance skeletal muscle mitochondrial function, and liver-secreted Notum promotes browning of white adipose tissue, also known as "beiging." We demonstrate the general applicability of the method by providing in vivo evidence for three additional novel molecules mediating tissue-tissue interactions.

Mouse Systems Genetics as a Prelude to Precision Medicine

“…There are various resources that provide access to the mouse systems genetics datasets (Table 1), as well as the systems approaches, including GeneNetwork (www.genenetwork.org), the Mouse Phenome Database (https://phenome.jax.org/), the Systems Genetics Resource (https://systems.genetics.ucla.edu/), the Attie Lab Diabetes Database (http://diabetes.wisc.edu/), the Diversity Outbred Database (www.jax.org/research-andfaculty/genetic-diversity-initiative/tools-data/diversity-outbred-database), the Swiss-BXD web interface (https://bxd.vital-it.ch), and Systems-Genetics.org (www.systems-genetics.org/). These systems genetics resources enable the possibility of reusing historically collected data to identify novel biological insights, such as those done previously [25,26,86,87].…”

“…Additional computational methods will surely emerge that exploit such huge datasets and a number of recent examples illustrate the power of such strategies. For instance, using transcriptome datasets obtained from different tissues of the HMDP cohort, a new strategy to identify important endocrine factors in the communication between tissues was developed ( Figure 5D) [87]. Using expression datasets from large cohort studies, novel systems approaches, including the GeneBridge toolset (www.systems-genetics.org), have also been developed to identify the novel function of genes or new members of pathway modules [100].…”

Inter‐organ communication: a gatekeeper for metabolic health

“…Increasing Lcn5 (LCN6 in humans) levels promotes insulin sensitivity by enhancing muscle function in murine DIO models [135] Metrnl Circulating Meteorin-like levels are significantly lower in T2D patients. Serum Metrnl is inversely correlated with fasting glucose in humans.…”

“…In the last decades, increasing efforts have been made to understand the mechanisms behind tissue communication. Omics approaches have been used to characterize novel molecules participating in interorgan communication, like Lcn5 and Notum [135], but more research is necessary to understand their role in normal physiology. These novel techniques will allow for the identification of novel players in inter-organ communication, but identifying their receptors/transporters, understanding their mechanism of action, and defining their target cell type(s) will captivate researchers in the field for the years to come.…”

Systems genetics applications in metabolism research

“…What factors mediate tissue-tissue cross-talk?-Metabolic homeostasis involves tight interactions across multiple tissues, but elucidating the nature of such tissue-tissue cross-talk has been challenging. Seldin and colleagues 59 have developed a statistical approach to identify novel tissue-tissue endocrine circuits by using expression data from multiple tissues of a mouse population ( Fig. 2b-e).…”